Abstract
Repression of glutamine metabolism by SIRT4 in response to DNA damage inhibits tumorigenesis.
Major finding: Repression of glutamine metabolism by SIRT4 in response to DNA damage inhibits tumorigenesis.
Mechanism: SIRT4 loss enhances glutamine-driven cancer cell proliferation and genomic instability.
Impact: SIRT4 expression is decreased in many human tumors and correlates with poor prognosis.
Dysregulation of the DNA damage response, which protects against genomic instability by triggering cell-cycle arrest and DNA repair, is commonly associated with tumorigenesis. Recent studies have shown that DNA damage also induces changes in cellular metabolism, including increased synthesis of nucleotide precursors to enable DNA repair, but the metabolic pathways that limit proliferation under these conditions are unknown. Jeong and colleagues found that genotoxic stress repressed glutamine consumption without affecting glucose uptake, resulting in reduced production of tricarboxylic acid (TCA) cycle intermediates in both primary and tumor cell lines. This repression of glutamine metabolism was mediated by the mitochondrial protein sirtuin 4 (SIRT4), which was upregulated in response to DNA-damaging agents in cell lines and normal lung tissue and impaired glutamine utilization by the TCA cycle. In contrast, SIRT4 deficiency enhanced glutamine incorporation into TCA cycle intermediates and prevented the suppression of mitochondrial glutamine uptake after DNA damage. Additionally, loss of SIRT4 impaired DNA damage–induced cell-cycle arrest and resulted in accumulation of DNA damage and increased aneuploidy, suggesting that SIRT4-dependent regulation of glutamine metabolism limits growth and protects cells from genomic instability under genotoxic stress. Consistent with this idea, SIRT4-deficient cells exhibited transformed phenotypes, including augmented proliferation and colony formation, which were suppressed by inhibition of glutamine metabolic enzymes. Furthermore, SIRT4 loss augmented allograft tumor growth and resulted in an age-dependent increase in spontaneous lung tumor formation, whereas SIRT4 reconstitution reduced glutamine uptake and repressed the proliferation and genomic instability of lung tumor cells. Decreased SIRT4 expression was also detected in several human cancers, particularly lung cancer, and was correlated with reduced survival. These findings identify SIRT4 as a tumor suppressor linking glutamine metabolism and genomic integrity and suggest that targeting of this metabolic pathway may be clinically beneficial.
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